Hereditary nonpolyposis colorectal cancer (HNPCC) is receiving major attention throughout the world (Lynch et al; Dis Colon Rect 24:311-322, 1981) and may account for as much as 5% of all colorectal cancer, exceeding the 1% estimate for all forms of its familial multiple adenomatous polyposis coli counterpart. Our efforts during more than two decades has provided many insights into this syndrome(s) which lacks premonitory clinical signs for its diagnosis. Nevertheless, the literature reflects much confusion with respect to its natural history, tumor spectrum, and surveillance/management. Our purpose is to maintain and extend the largest HNPCC family resource of its type in the world, in the hope of further elucidating the multifaceted complexities about this disease(s). The resource comprises 23 variably extended families wherein detailed medical information and family histories have been compiled on approximately 4000 individuals. The work plan will include: 1) updating the pedigrees as new cancers occur in order to more fully assess each individual's true cancer risk; 2) provision of continued medical/genetic counselling to family members; 3) elucidation of genetic heterogeneity with particular reference to tumor complement in HNPCC; 4) education of both family members and their private physicians about the risk of cancer and its highly targeted surveillance/management strategies based upon clinical nuances of natural history; 5) clearer biostatistical elucidation of genetic heterogeneity with particular attention to extracolonic tumors, early age of onset, multiple primary cancers, predilection of proximal vs. distal colonic cancer, cutaneous signs, and increased cancer survival; and 6) assuring an opportunity for supply of vital medical/genetic data and biological samples to collaborating geneticists, biostatisticians, and other basic scientists concerned with a variety of parameters which could provide clues to biomarkers of gene carriage. A segregation analysis was done on 11 families. Both the recessive hypothesis and the hypothesis of no transmission were rejected (p less than 0.001). The data showed a good fit with the hypothesis of dominant transmission with variable age of onset. This proposal will extend the initial segregation analysis and provide an analysis of family syndromes, to determine which particular cancer phenotypes form familial syndromes.